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A number of genetic alterations have recently been linked to papillary thyroid carcinomas; BRAF activating mutations being the most common, amounting from 35% to 83% (Cohen et al., 2004; Cohen et al., 2003; Finkelstein et al., 2012; Y. E. Nikiforov, 2011; Trovisco et al., 2006). More than 90% of these involve a thymine to adenine mutation in exon 15, resulting in a valine to glutamine substitution in the BRAF protein (V600E).
The assessment of the BRAF status contributes to prognosis and treatment of papillary carcinoma (Kabaker et al., 2012; Lassalle et al., 2010; Nucera et al., 2012; Pizzolanti et al., 2007; Xing et al., 2009), since it has been shown to relate to lymph node or distant metastasis, higher tumor staging, recurrence and treatment failure (He et al., 2014; Mekel et al., 2010; Rossi et al., 2013; Xing et al., 2005). Moreover, in cytological material, detection of BRAF mutations is useful in the diagnosis of papillary carcinoma. Because BRAF test has high specificity for PTCs, especially for classic and tall cell variants, in contrast BRAF mutations are not found in benign lesions and follicular neoplasms (Y. Nikiforov, 2012).
Recently, in histological sections it has been shown that specific morphologic characteristics could be correlated to BRAF activated PTCs (Finkelstein et al., 2012; Virk et al., 2014; Virk et al., 2013). However, there is no experience in cytological material, neither involvement of morphometric evaluation nor application of machine-based classification.
The aim of this study was to investigate if in ThinPrep® cytopreparations from thyroid PTC Fine Needle Aspirations (FNAs), is feasible to identify significant morphometric characteristics related to BRAF mutations. Specifically, after applying image morphometry on cell nuclei, and subsequently, a Classification And Regression Tree (CART) algorithm, the focus was on three topics:
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To identify the most appropriate morphometric features to use in order to characterize if a nucleus expresses BRAF mutations.
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To quantify each individual criterion.
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To produce an algorithm, that exploits morphometric criteria via CARTs in order to predict the BRAF status of a PTC case.
If there is evidence that this is feasible, then there is an open road for three applications:
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Use of digital images to perform an examination that is currently based on molecular biology methods.
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Use a telemedicine environment to remotely identify BRAF V600E mutations as digital images is possible to be transmitted via communication channels.
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Application of quality control and assurance locally or at distance by comparing the results of PCR-based methods and the proposing digital methodology. Definitely, in order to ensure quality, all the steps of the process should be standardized. Thus, emphasis should be given to minimizing human intervention, in this study this ranged from the biological sample collection, and transportation down to the measurements evaluation by a computerized system.